Developing extracellular vesicle based therapeutics against pre-term birth through the use of maternal-fetal interface on a chip

摘要 自发性早产（PTB）约占所有早产的60%（1500万PTB/年和100万PTB/年）。 地球仪周围的新生儿死亡）。胎儿和母体间室的平衡免疫稳态确保 妊娠维持和胎儿-胎盘生长。过早破坏免疫稳态， 由于感染性或其他非感染性风险因素引起的压倒性宿主炎症反应导致大多数 的PTB。在过去的几十年里，PTB的发病率没有下降，目前的PTB预防策略也没有下降。 解决胎儿免疫反应，一个关键的调解人，触发早产。该提案小组最近 使用一种创新的技术来设计外泌体，使其富含NF-κB抑制剂，称为超级抑制剂。 阻遏物IκBα [SR]。使用转基因小鼠模型的初步研究显示，PTB成功延迟， 与胎儿-母体界面组织（F-M;胎儿）炎症减少相关的副作用 膜细胞和母体蜕膜）。然而，将其转移到下一阶段是具有挑战性的， 许多非人类灵长类动物，最接近人类F-M界面的动物模型，将被 需要，这是成本高昂的。一个器官芯片（OOC）模型，忠实地代表了结构， 人类F-M界面的功能和响应可以克服这些挑战。提案团队已 最近报道了第一个F-M接口OOC模型，该模型成功地用于显示交互和 原代细胞的过渡特性，类似于它们在子宫内的生物学功能。在UG 3阶段，该模型 将扩展到包括完整的F-M界面，重新创建健康和疾病炎症状态， 证实了它们的细胞功能和易患PTB的反应。UG 3的目标是：目标1验证 目的2建立疾病F-M界面OOC模型。UH 3的目标是： 目的3检测细胞外囊泡（EV）编码的实验性药物NF-κ B阻遏物（SR）在正常人和正常人外周血中的表达。 疾病F-M界面OOC模型;目的4使用OOC模型进行临床前试验，以研究 种族多样性和胎儿性别对实验药物疗效的影响。成功 提出的研究将产生一个个性化的F-M接口OOC模型，可以模仿健康或 妊娠的疾病状态，其可用于测试候选治疗分子的作用，以加速妊娠的进展。 临床试验和/或消除/最大限度地减少昂贵的临床试验的某些步骤。

ABSTRACT Spontaneous preterm birth (PTB) accounts for ~60% of all preterm births (15 million PTBs/year and 1 million neonatal deaths around the globe). Balanced immune homeostasis by fetal and maternal compartments ensure pregnancy maintenance and feto-placental growth. Premature disruption of immune homeostasis and overwhelming host inflammatory response due to infectious or other non-infectious risk factors lead to majority of PTBs. PTB rate has not declined in the past several decades, and current PTB prevention strategies do not address fetal immune responses, a key mediator that triggers preterm labor. The proposing team has recently used an innovative technology to engineer exosomes to be enriched with an inhibitor to NF-κB, termed as super repressor IκBα [SR]. Pilot studies using a transgenic mouse model showed successful delay in PTB without any side effects that was associated with reduction in inflammation at the feto-maternal interface tissues (F-M; fetal membrane cells and maternal decidua). However, moving this to the next stage is challenging, as a very large number of non-human primates, the animal model that most closely resemble the human F-M interface, will be needed, which is cost prohibitive. An organ-on-chip (OOC) model that faithfully represents the structure, functions, and responses of human F-M interface can overcome such challenges. The proposing team has recently reported the first F-M interface OOC model, which was successfully utilized to show the interactive and transitional properties of primary cells, resembling their biological functions in utero. In the UG3 phase, this model will be expanded to include the full F-M interface, recreate a healthy and disease inflammatory state, and fully validated for their cellular functions and responses predisposing to PTB. The UG3 aims are: Aim 1 To validate the F-M interface OOC model; Aim 2 To establish disease F-M interface OOC models. The UH3 aims are: Aim 3 To test extracellular vesicle (EV)-encoded experimental drug NF-kB repressor (SR) on normal and disease F-M interface OOC models; Aim 4 Conduct pre-clinical trial using the OOC model to investigate the impact of racial diversity and gender of fetus on the efficacy of the experimental drug. The success of the proposed research will produce a personalized F-M interface OOC model that can mimic either healthy or disease state of pregnancy, which can be used to test the effect of candidate therapeutic molecules to expedite processes towards clinical trials and or eliminate/minimize certain steps from expensive clinical trials.